Fulcrum Therapeutics Inc (FULC) 2023 Q1 法說會逐字稿

Good morning and welcome to the Fulcrum Therapeutics First Quarter 2023 Financial Results and Business Update conference call. (Operator Instructions) This call is being webcast live on the Investors section of Fulcrum's website at www.fulcrumtx.com and is being recorded. For opening remarks, I would like to introduce Chris Calabrese. Please go ahead.

早上好，歡迎參加 Fulcrum Therapeutics 2023 年第一季度財務業績和業務更新電話會議。 （操作員說明）本次電話會議正在 Fulcrum 網站 www.fulcrumtx.com 的投資者部分進行網絡直播並進行錄音。作為開場白，我想介紹一下克里斯·卡拉布雷斯。請繼續。

Thank you, and good morning. Welcome to the Fulcrum Therapeutics First Quarter 2023 Financial Results and Business Update Conference Call. Please be reminded that remarks made during this call may contain forward-looking statements within the meeting of the Private Securities Litigation Reform Act of 1995. These may include statements about the company's future expectations and plans including the clinical hold of FTX-6058, clinical development time lines and financial projections. While these forward-looking statements represent Fulcrum's views as of today, they should not be relied upon as representing the company's views in the future.

謝謝你，早上好。歡迎參加 Fulcrum Therapeutics 2023 年第一季度財務業績和業務更新電話會議。請注意，本次電話會議期間發表的言論可能包含 1995 年《私人證券訴訟改革法案》會議中的前瞻性陳述。這些陳述可能包括有關公司未來預期和計劃的陳述，包括 FTX-6058 的臨床持有、臨床開發時間表和財務預測。雖然這些前瞻性陳述代表 Fulcrum 目前的觀點，但不應依賴它們代表公司未來的觀點。

Fulcrum may update these statements in the future, but is not taking on an obligation to do so. Please refer to Fulcrum's most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business. Leading the call today will be Dr. Robert Gould, Interim Chief Executive Officer, Fulcrum, who will provide a corporate overview, discuss key pipeline updates as well as the financials before we open the call for Q&A. And Dr. Iain Fraser, Interim Chief Medical Officer, will be able to answer questions during the Q&A portion of the call. With that, it's my pleasure to turn the call over to Robert.

Fulcrum 可能會在未來更新這些聲明，但不承擔這樣做的義務。請參閱 Fulcrum 最近向美國證券交易委員會提交的文件，了解與該公司業務相關的某些風險和不確定性的討論。今天的電話會議將由 Fulcrum 臨時首席執行官 Robert Gould 博士主持，他將在我們開始問答電話會議之前提供公司概況、討論關鍵管道更新以及財務狀況。臨時首席醫療官 Iain Fraser 博士將能夠在電話問答部分回答問題。至此，我很高興將電話轉給羅伯特。

Thank you, Chris. Good morning. I appreciate everyone taking the time to join us today. I would like to begin by reiterating our deep commitment to advancing our organization and improving the lives of patients with genetically defined diseases in areas of high unmet medical need. In the first few months of 2023, we continue to make progress to address the FTX-6058 clinical hold and advance our Phase III REACH trial of losmapimod in facioscapulohumeral muscular dystrophy.

謝謝你，克里斯。早上好。我感謝大家今天抽出時間加入我們。首先，我想重申我們對推進我們的組織和改善醫療需求未得到滿足的地區患有遺傳性疾病的患者的生活的堅定承諾。 2023 年前幾個月，我們將繼續在解決 FTX-6058 臨床擱置問題上取得進展，並推進洛斯馬莫德治療面肩肱型肌營養不良症的 III 期 REACH 試驗。

We are also pleased to announce the appointment of Alex Sapir to the position of President and Chief Executive Officer and member of the Board of Directors effective July 1, 2023. As of last Friday, Alex joined a special adviser to me and we are thrilled to have a world-class leader of his stature on board to propel Fulcrum to the next level of achievement. Alex brings deep industry knowledge from the public sector and has more than 25 years of experience building commercial stage pharmaceutical organizations.

我們還很高興地宣布任命 Alex Sapir 擔任總裁兼首席執行官和董事會成員，自 2023 年 7 月 1 日起生效。自上週五起，Alex 成為我的特別顧問，我們很高興擁有與他同等地位的世界級領導者將推動 Fulcrum 取得新的成就。 Alex 帶來了公共部門深厚的行業知識，並擁有超過 25 年建立商業階段製藥組織的經驗。

Most recently, Alex served as Chief Executive Officer and a member of the Board of Directors of ReViral prior to the company's acquisition by Pfizer. Prior to ReViral, Alex served as President, Chief Executive Officer and member of the Board of Directors of Dova Pharmaceuticals. Earlier in his career, Alex spent 10 years as Executive Vice President of Marketing and Sales for United Therapeutics and held roles of increasing responsibility within the commercial organization at GlaxoSmithKline. Alex's impressive track record makes him an ideal fit for Fulcrum at this critical juncture. With this brief introduction, I'll now dive into our programs and provide an update on recent activities.

最近，在 ReViral 被輝瑞收購之前，Alex 擔任該公司的首席執行官和董事會成員。在加入 ReViral 之前，Alex 曾擔任 Dova Pharmaceuticals 的總裁、首席執行官和董事會成員。在其職業生涯早期，Alex 在 United Therapeutics 擔任了 10 年的營銷和銷售執行副總裁，並在葛蘭素史克的商業組織中擔任過越來越重要的職務。 Alex 令人印象深刻的業績記錄使他成為 Fulcrum 在這個關鍵時刻的理想人選。通過這個簡短的介紹，我現在將深入了解我們的計劃並提供最近活動的最新信息。

Let me start by discussing our most recent updates to the FTX-6058 program. Our oral HbF inducer for the potential treatment of patients with sickle cell disease. As previously announced, we received verbal notification from the FDA on February 23 that they had placed a full clinical hold on the investigational new drug application for FTX-6058 and we received a formal clinical hold letter from the FDA on February 24. We immediately suspended dosing and paused enrollment in the trial of FTX-6058. We have been in active and ongoing dialogue with the FDA and we'll provide an update once we have more clarity on the regulatory path forward. Overall, our interactions with the agency thus far have been productive and collaborative, and we look forward to continue our dialogue as we work to resolve the clinical hold.

首先讓我討論一下我們對 FTX-6058 計劃的最新更新。我們的口服 HbF 誘導劑可用於治療鐮狀細胞病患者。正如之前所宣布的，我們於 2 月 23 日收到 FDA 的口頭通知，稱他們已對 FTX-6058 的研究性新藥申請進行全面臨床擱置，我們於 2 月 24 日收到 FDA 的正式臨床擱置信。我們立即暫停FTX-6058 試驗中的給藥和暫停招募。我們一直在與 FDA 進行積極、持續的對話，一旦我們對未來的監管路徑有了更清晰的了解，我們將提供最新信息。總體而言，到目前為止，我們與該機構的互動是富有成效和協作的，我們期待在努力解決臨床擱置問題時繼續進行對話。

An initial feedback provided in February 2023, the FDA stated that the hold related to preclinical data submitted in April, October and December 2022 and nonclinical and clinical evidence of hematologic malignancies observed with other inhibitors of polycomb repressive complex 2 or PRC2.

FDA 於 2023 年 2 月提供初步反饋，表示暫停與 2022 年 4 月、10 月和 2022 年 12 月提交的臨床前數據以及使用多梳抑制複合物 2 或 PRC2 的其他抑製劑觀察到的血液惡性腫瘤的非臨床和臨床證據有關。

The agency is focused on balancing the safety and efficacy trade-offs and has requested that Fulcrum further define the population where the potential benefit of continued treatment with FTX-6058 outweighs potential risk. The hold is not a result of any clinical findings in the Phase Ib trial that was ongoing at the time of the hold. For further context, we have a strong data set from the subjects who completed dosing prior to the clinical hold. Treatment with FTX-6058, the highest dose of 12 milligram showed a 10% absolute HbF increase from baseline, resulting in a total HbF level of 24.9% after 42 days of treatment.

該機構專注於平衡安全性和有效性的權衡，並要求 Fulcrum 進一步定義繼續使用 FTX-6058 治療的潛在益處超過潛在風險的人群。暫停並不是由於暫停時正在進行的 Ib 期試驗中任何臨床發現的結果。為了進一步了解背景，我們擁有來自臨床暫停前完成給藥的受試者的強大數據集。使用 FTX-6058 治療，最高劑量 12 毫克，顯示 HbF 較基線絕對增加 10%，治療 42 天后總 HbF 水平達到 24.9%。

Additionally, FTX-6058 has been generally well tolerated to date with no drug-related treatment emergent serious adverse events or discontinuations due to treatment-emergent adverse events. All adhering subjects showed clinically relevant improvements in the 6- and 12-milligram dose cohorts, consistent across subjects, both on and off background hydroxyurea, the current standard of care. We maintain that FTX-6058 has the potential to provide a differentiated therapeutic option for people living with sickle cell disease and that the clinical and preclinical data generated to date demonstrate a favorable benefit risk profile.

此外，迄今為止，FTX-6058 總體耐受性良好，沒有出現與藥物相關的治療出現的嚴重不良事件或因治療出現的不良事件而停藥的情況。所有堅持治療的受試者在 6 毫克和 12 毫克劑量組中均表現出臨床相關的改善，在使用羥基脲（目前的護理標準）和非背景羥基脲的情況下，受試者之間的情況一致。我們認為，FTX-6058 有潛力為鐮狀細胞病患者提供差異化的治療選擇，並且迄今為止生成的臨床和臨床前數據表明了良好的獲益風險狀況。

Now turning to our most advanced program, losmapimod, a selective p38 alpha beta mitogen-activated protein kinase inhibitor. Losmapimod is in Phase III development for the treatment of FSHD, an autosomal dominant genetic form of muscular dystrophy, which has an estimated patient population of 16,000 to 38,000 in the United States alone. FSHD is characterized by relentless and accumulating muscle and functional loss and results in the inability to perform daily life activities due to a significant impairment of upper extremity function, loss of mobility and chronic pain.

現在轉向我們最先進的程序，losmapimod，一種選擇性 p38 α β 絲裂原激活蛋白激酶抑製劑。 Losmapimod 正處於用於治療 FSHD 的 III 期開發階段，FSHD 是一種常染色體顯性遺傳形式的肌營養不良症，僅在美國估計就有 16,000 至 38,000 名患者。 FSHD 的特點是不斷累積的肌肉和功能喪失，並由於上肢功能嚴重受損、活動能力喪失和慢性疼痛而導致無法進行日常生活活動。

Although it's one of the most common forms of muscular dystrophy, there are currently no approved treatments. Given the high unmet need for innovation, we are extremely encouraged by losmapimod's therapeutic potential to preserve muscle function and believe it has the potential to address the urgent need for a safe and effective disease-modifying treatment that can slow or stop disease progression.

儘管它是最常見的肌營養不良症之一，但目前尚無批准的治療方法。鑑於對創新的需求尚未得到滿足，我們對洛斯馬莫德保持肌肉功能的治療潛力感到非常鼓舞，並相信它有潛力滿足對安全有效的疾病緩解治療的迫切需求，從而減緩或阻止疾病進展。

We initiated reach our double-blind placebo-controlled Phase III trial of losmapimod in June 2022 and are currently enrolling patients in the U.S., Canada and Europe. At this time, 31 sites are active out of 36 sites. This 48-week trial is expected to enroll approximately 230 adults and expected to complete enrollment in the second half of 2023. We are pleased with the rapid pace of enrollment in the losmapimod Phase III REACH trial, which is both a testament to the high level of engagement by our clinical trial sites and our team's strategic execution. The primary end point is the absolute change from baseline in reachable workspace or RWS, a quantitative measure of upper extremity, range of motion and function that specifically evaluate shoulder and proximal arm mobility with 3D motion sensor technology.

我們於 2022 年 6 月啟動了 losmapimod 的雙盲安慰劑對照 III 期試驗，目前正在美國、加拿大和歐洲招募患者。此時，36 個站點中有 31 個站點處於活動狀態。這項為期 48 週的試驗預計將招募約 230 名成人，並預計於 2023 年下半年完成招募。我們對 losmapimod III 期 REACH 試驗的快速招募速度感到滿意，這既證明了高水平我們的臨床試驗中心的參與和我們團隊的戰略執行。主要終點是可達工作空間或 RWS 相對於基線的絕對變化，這是上肢、運動範圍和功能的定量測量，專門利用 3D 運動傳感器技術評估肩部和近端手臂的活動能力。

Preserving this upper extremity function is critical for maintaining the ability for self-care and other activities of daily living that directly influence quality of life and independence. In addition to safety and tolerability, secondary endpoints include muscle fat infiltration or MFI, an important marker of disease pathology and self-reported outcome such as the Patient Global Impression of Change, or PGIC and quality of life measures. These will include healthcare utilization questionnaires that will inform our thinking about payer strategy as we prepare for a potential commercial launch.

保留這種上肢功能對於維持自我護理和其他直接影響生活質量和獨立性的日常生活活動的能力至關重要。除了安全性和耐受性之外，次要終點還包括肌肉脂肪浸潤（MFI），這是疾病病理學和自我報告結果的重要標誌，例如患者總體變化印象（PGIC）和生活質量指標。這些將包括醫療保健利用調查問卷，在我們準備潛在的商業發佈時，這些調查問卷將告知我們對付款人策略的思考。

REACH was designed as a highly efficient 48-week trial and is intended to be registration enabling both in the U.S. and in ex-U.S. geography. We are confident that we have selected reliable measures of disease progression and we hope to demonstrate meaningful advantages for losmapimod compared to placebo.

REACH 被設計為一項為期 48 週的高效試驗，旨在在美國和美國以外地區進行註冊。地理。我們相信我們已經選擇了可靠的疾病進展測量方法，我們希望能夠證明洛斯馬莫德相對於安慰劑具有有意義的優勢。

Encouragingly, our Phase IIb ReDUX4 trial demonstrated significant improvements in RWS relative to placebo at 48 weeks. Furthermore, top line results from the ongoing open-label extension of ReDUX4 shows that participants in the initial treatment arm who continued to receive losmapimod demonstrated durability of effect through a 96-week period. Additionally, patients who crossed over from placebo to losmapimod after the initial 48-week trial period showed improvement in slowing of disease progression as measured by RWS mean change from baseline. We believe these data support the disease-modifying potential and long-term benefit of losmapimod.

令人鼓舞的是，我們的 IIb 期 ReDUX4 試驗表明，在 48 週時，RWS 相對於安慰劑有顯著改善。此外，ReDUX4 正在進行的開放標籤擴展的主要結果顯示，繼續接受洛斯馬莫德治療的初始治療組參與者在 96 週內表現出效果的持久性。此外，在最初的 48 週試驗期後，從安慰劑過渡到洛斯馬莫德的患者顯示，根據 RWS 相對於基線的平均變化來衡量，疾病進展速度有所改善。我們相信這些數據支持洛斯馬莫德的疾病緩解潛力和長期益處。

To date, losmapimod has been dosed in over 3,600 patients across multiple therapeutic areas and results from ReDUX4 and our open-label extension trial provides evidence of an encouraging safety and tolerability profile. As we drive our clinical path forward for losmapimod, we look forward to leveraging the large safety database and building on our learnings from ReDUX4, an ongoing open-label extension trial. Now turning to other corporate matters. As previously announced, Esther Rajavelu, our Chief Financial Officer, recently resigned from the company effective April 21, 2023. We appreciate her commitment to operational and financial excellence and are grateful for the positive contribution she has made to our company.

迄今為止，losmapimod 已在多個治療領域對 3,600 多名患者進行了給藥，ReDUX4 的結果和我們的開放標籤擴展試驗提供了令人鼓舞的安全性和耐受性概況的證據。當我們推動 Losmapimod 的臨床道路前進時，我們期待利用大型安全數據庫並藉鑑 ReDUX4（一項正在進行的開放標籤擴展試驗）的經驗教訓。現在轉向其他公司事務。正如之前宣布的，我們的首席財務官 Esther Rajavelu 最近從公司辭職，生效日期為 2023 年 4 月 21 日。我們感謝她對卓越運營和財務的承諾，並感謝她為我們公司做出的積極貢獻。

We are continuing to work with Esther in her role as an adviser, while the finance team continues to execute our financial strategy. As a reminder, Dr. Iain Fraser continues to serve as Interim CMO and Dr. Alan Ezekowitz, member of the Fulcrum Board of Directors since February 2017 continues to serve as Senior Clinical Adviser to ensure program continuity. As we continue to solidify our leadership team, we remain focused on realizing Fulcrum's mission and the work at hand. With that, I will provide an update on our financials. We ended March 31, 2023, with cash, cash equivalents and marketable securities of $297.8 million compared to $202.9 million on December 31, 2022. In January 2023, we completed an underwritten public offering of our common stock, raising approximately $117.3 million in net proceeds. We continue to operate from a strong financial position and we expect our cash, cash equivalents and marketable securities to fund our operating expenses into mid-2025. This projection assumes the timely resolution of the FTX-6058 clinical hold.

我們將繼續與以顧問身份的 Esther 合作，而財務團隊將繼續執行我們的財務戰略。謹此提醒，Iain Fraser 博士繼續擔任臨時 CMO，自 2017 年 2 月起擔任 Fulcrum 董事會成員的 Alan Ezekowitz 博士繼續擔任高級臨床顧問，以確保項目的連續性。隨著我們繼續鞏固我們的領導團隊，我們仍然專注於實現 Fulcrum 的使命和手頭的工作。接下來，我將提供有關我們財務狀況的最新信息。截至 2023 年 3 月 31 日，我們的現金、現金等價物和有價證券為 2.978 億美元，而 2022 年 12 月 31 日為 2.029 億美元。2023 年 1 月，我們完成了普通股的承銷公開發行，籌集了約 1.173 億美元的淨收益。我們將繼續以強勁的財務狀況運營，預計我們的現金、現金等價物和有價證券將為我們的運營費用提供資金直至 2025 年中期。該預測假設 FTX-6058 臨床擱置的及時解決。

Collaboration revenue was $0.3 million for the first quarter of 2023 as compared to $2.6 million for the first quarter of 2022. Research and Development expenses were $16.7 million for the first quarter of 2023 as compared to $17.8 million for the first quarter of 2022. The decrease of $1.1 million was primarily due to decreased research and development headcount, partially offset by increased costs associated with the advancement of reach.

2023 年第一季度的合作收入為 30 萬美元，而 2022 年第一季度為 260 萬美元。2023 年第一季度的研發費用為 1,670 萬美元，而 2022 年第一季度為 1,780 萬美元。 110 萬美元的損失主要是由於研發人員數量減少，部分被與擴大覆蓋範圍相關的成本增加所抵消。

General and administrative expenses were $11.5 million for the first quarter of 2023 as compared to $10.8 million for the first quarter of 2022. The increase of $0.7 million was primarily due to increased stock-based compensation expense. Net loss was $24.8 million for the first quarter of 2023 as compared to $25.9 million for the first quarter of 2022. Overall, I am confident the company's strong cash position and upcoming catalysts provide a solid foundation for execution and value creation.

2023 年第一季度的一般及管理費用為 1,150 萬美元，而 2022 年第一季度為 1,080 萬美元。增加 70 萬美元主要是由於股票薪酬費用增加。 2023 年第一季度的淨虧損為 2480 萬美元，而 2022 年第一季度的淨虧損為 2590 萬美元。總體而言，我相信公司強勁的現金狀況和即將推出的催化劑為執行和價值創造奠定了堅實的基礎。

We remain focused on driving our clinical programs forward, exploring opportunities to leverage the value of our research engine and executing our corporate objectives. We remain on track to complete enrollment for our FSHD Phase III REACH trial in the second half of 2023 and are committed to working with the FDA to resolve the clinical hold on FTX-6058. I want to reiterate that we are optimistic there is a path forward to resolve the full clinical hold. Additionally, with today's announcement of Alex as our next CEO and President, Fulcrum is ending the first quarter of 2023 in a position of strength and great promise for the future.

我們仍然專注於推動我們的臨床項目向前發展，探索利用我們研究引擎價值的機會並執行我們的企業目標。我們仍有望在 2023 年下半年完成 FSHD III 期 REACH 試驗的註冊，並致力於與 FDA 合作解決 FTX-6058 的臨床擱置問題。我想重申，我們對解決全面臨床擱置問題的解決辦法持樂觀態度。此外，隨著今天宣布 Alex 擔任我們的下一任首席執行官兼總裁，Fulcrum 在 2023 年第一季度結束時處於強勢地位，對未來充滿希望。

Before we conclude today's call, I want to extend my sincere appreciation and gratitude for the foundational work that has brought us closer to treating the root cause of genetically defined rare diseases and bringing transformative therapies to patients. I would like to thank the entire Fulcrum team, our investors and the many people who have been supportive along the way, including our patients and their families. With that, we are happy to take questions.

在我們結束今天的電話會議之前，我想對我們所做的基礎工作表示誠摯的讚賞和感謝，這些工作使我們更接近於治療基因罕見疾病的根本原因，並為患者帶來變革性療法。我要感謝整個 Fulcrum 團隊、我們的投資者以及一路以來給予支持的許多人，包括我們的患者及其家人。因此，我們很樂意回答問題。

(Operator Instructions) The first question comes from Edward Tenthoff with Piper Sandler.

（操作員說明）第一個問題來自 Edward Tenthoff 和 Piper Sandler。

Robert, thank you for the thorough update. I wanted to dig a touch deeper into 6058 then sort of what are the outstanding issues? What do you see as sort of the experiments you need to do or data you need to collect in order to provide the FDA with the information they need to list the whole take?

羅伯特，感謝您的徹底更新。我想更深入地了解 6058，那麼有哪些突出的問題呢？您認為您需要做哪些實驗或需要收集哪些數據，以便向 FDA 提供列出全部內容所需的信息？

Thanks, Ed. There are two outstanding issues with the FDA that we're currently in discussions with them. One is the question around reversibility of the effect that we see when we inhibit EED with 6058. That's primarily related to reversibility of gene expression changes, which of course are consequences inhibiting the EED protein. Those studies are preclinical nontoxicology studies along the lines of pharmacologic reversibility. They are well underway. And as we get those results, we'll be discussing them with the FDA. The other set of outstanding issues relates to defining the patient populations that can most benefit from the elevation in HbF that we're seeing.

謝謝，艾德。我們目前正在與 FDA 討論兩個懸而未決的問題。其中一個問題是，當我們用 6058 抑制 EED 時，我們所看到的效果的可逆性。這主要與基因表達變化的可逆性有關，這當然是抑制 EED 蛋白的後果。這些研究是沿著藥理學可逆性的臨床前非毒理學研究。他們進展順利。當我們得到這些結果時，我們將與 FDA 進行討論。另一組突出的問題涉及確定最能從我們所看到的 HbF 升高中受益的患者群體。

The regulatory agency has asked us to define that population, a higher-risk population than we were evaluating previously and we're in active discussions with them to discuss that population. As I'm sure you know, there have been a number of different definitions of at-risk population in sickle cell patients, whether you're looking at the gene and cell therapy studies or some of the other small molecules that are symptomatic treatments. And so we're integrating those prior studies along with our own thoughts to define that population that can most benefit.

監管機構要求我們定義該人群，即比我們之前評估的風險更高的人群，我們正在與他們積極討論該人群。我相信您知道，對於鐮狀細胞病患者的高危人群有許多不同的定義，無論您是在研究基因和細胞治療研究，還是其他一些對症治療的小分子。因此，我們將之前的研究與我們自己的想法結合起來，以確定最能受益的人群。

That makes a lot of sense. One last quick question, if I may and this may be a tough one to answer. Is there a dose relationship to the concerns of the FDA has or since this really is in clinical finding, is there not some kind of dose relationship that tox concerns spread...

這很有意義。最後一個簡單的問題，如果可以的話，這可能是一個很難回答的問題。是否與 FDA 的擔憂存在劑量關係，或者由於這確實是在臨床發現中，是否不存在某種毒性擔憂傳播的劑量關係......

Yes. So we've not seen anything in the clinical studies that would give us any concern about the toxicologic findings that have been seen preclinically. As I mentioned during the update was at the 2, 6 and 12 milligram clinical doses, there have been no serious adverse events at all. And in terms of the preclinical studies, we see dose-dependent increases in target engagement. And part of the FDA's concern around the hematologic malignancies that we've seen is that those types of malignancies have been seen with other PRC2 inhibitors, and I want to be sure that we're defining that risk-benefit ratio appropriately, both preclinically as well as clinically.

是的。因此，我們在臨床研究中沒有看到任何可以讓我們對臨床前發現的毒理學結果產生任何擔憂的內容。正如我在更新期間提到的，在 2、6 和 12 毫克臨床劑量下，根本沒有出現嚴重的不良事件。就臨床前研究而言，我們看到目標參與度呈劑量依賴性增加。 FDA 對我們所看到的血液系統惡性腫瘤的部分擔憂是，這些類型的惡性腫瘤也曾在其他 PRC2 抑製劑中出現過，我想確保我們正確地定義了該風險效益比，無論是在臨床前還是在臨床前，以及臨床上。

Yes. That's helpful. And Robert, if I may just take them, congrats on finding him as CEO, a great job stepping in during this sort of transition time for the company.

是的。這很有幫助。羅伯特，如果我可以接受的話，恭喜他成為首席執行官，在公司的這種過渡時期，他的工作非常出色。

(Operator Instructions) The next question comes from Joseph Schwartz with SVB Securities.

（操作員說明）下一個問題來自 SVB 證券公司的 Joseph Schwartz。

I was wondering if you have any data on hand, which can help distinguish the propensity of FTX-6058 to cause heme malignancies relative to other PRC2 inhibitors, that you're able to show to the FDA in order to help them get comfortable with the risks and benefits of 6058 in sickle cell disease. And as a follow-up, how are you thinking about defining the patient population who can benefit? And is that high risk?

我想知道您手頭是否有任何數據，這些數據可以幫助區分 FTX-6058 相對於其他 PRC2 抑製劑導致血紅素惡性腫瘤的傾向，您可以向 FDA 展示這些數據，以幫助他們熟悉 FTX-6058 的使用情況。 6058 在鐮狀細胞病中的風險和益處。作為後續行動，您如何考慮定義可以受益的患者群體？那風險高嗎？

Maybe I'll take the first part of that, the first question that you asked and then let Iain speak to the second defining the patient population. Among the data that we've been able to share with the FDA is, of course, not only the studies that we've done -- the toxicology studies that we've done, but also the gene expression changes that we are seeing with EED inhibition in the animal studies, particularly the most towns model, animal studies. What we've seen there is that there's other -- obviously, are a number of gene expression changes. We're seeing really, as you would expect, robust effects on the HbF gene and HPV. And that's what the FDA is really focused on in terms of the reversibility studies. And so those kinds of gene expression changes relative to other inhibitors of PRC2 or what they're focusing on and maybe you want to speak to defining the patient population.

也許我會回答第一部分，即您提出的第一個問題，然後讓伊恩談談定義患者群體的第二個問題。當然，我們能夠與 FDA 分享的數據不僅包括我們所做的研究——我們所做的毒理學研究，還有我們看到的基因表達變化EED抑制在動物研究中，特別是大多數城鎮模型動物研究。我們所看到的是，顯然還有其他一些基因表達的變化。正如您所期望的那樣，我們確實看到了對 HbF 基因和 HPV 的強大影響。這就是 FDA 在可逆性研究方面真正關注的重點。因此，這些類型的基因表達相對於其他 PRC2 抑製劑或他們所關注的內容髮生了變化，也許您想談談定義患者群體。

Yes. Thanks, Robert, and thanks, Joseph, for the question. So based on the clinical data that we've generated to date, we've been able to see that subjects treated with FTX-6058 experience a dose dependence and clinically relevant increase in their fetal hemoglobin into the range where we think that this is going to be clinically relevant and potentially beneficial. We will discuss these aspects with the FDA as we explore our path forward. And as we think about populations for the clinical trial, we've been informed greatly by the therapies in the field including gene therapy and stem cell replacement therapies, gene editing and so on, where a higher-risk population has been defined in those studies.

是的。謝謝羅伯特，也謝謝約瑟夫提出的問題。因此，根據我們迄今為止生成的臨床數據，我們已經能夠看到接受 FTX-6058 治療的受試者出現劑量依賴性，並且胎兒血紅蛋白的臨床相關增加達到了我們認為的範圍具有臨床相關性和潛在益處。在探索前進道路時，我們將與 FDA 討論這些方面。當我們考慮臨床試驗的人群時，我們從該領域的療法中獲得了很多信息，包括基因療法和乾細胞替代療法、基因編輯等，這些研究中已經定義了高風險人群。

(Operator Instructions) The next question comes from Madhu Kumar with Goldman Sachs.

（操作員說明）下一個問題來自高盛的 Madhu Kumar。

This is Rob on for Madhu. And we were just wondering, are there any thoughts to new asset INDs given your cash runway?

我是羅布（Madhu）。我們只是想知道，考慮到您的現金跑道，對新資產 IND 有什麼想法嗎？

Thanks, Rob. Yes, we actually under the leadership of our Chief Scientific Officer, Jeff Jacobs or JJ as he goes by. We've got a number of options that are progressing through the preclinical programs. We're not quite ready to give updates on the status of those programs or the areas, but we continue to be focused on the nonmalignant hematology space in the muscular dystrophy space and in as Alex comes on board and has a chance to come up to speed on those programs, we're excited about providing further updates on what those programs are and their development status.

謝謝，羅布。是的，我們實際上是在首席科學官 Jeff Jacobs 或 JJ 的領導下進行的。我們有許多選項正在臨床前項目中取得進展。我們還沒有準備好提供這些項目或領域的最新狀態，但我們將繼續關注肌肉萎縮症領域的非惡性血液學領域，並且隨著 Alex 的加入並有機會參與進來由於這些計劃的進展速度很快，我們很高興能夠提供有關這些計劃的內容及其開發狀態的進一步更新。

Okay. Is there a time line that we can expect for sort of communication of the new INDs?

好的。新 IND 的溝通是否有預期的時間表？

Not yet. It's a little premature for us to speculate on that already provide guidance on those time lines.

還沒有。我們現在推測已經為這些時間表提供了指導還為時過早。

(Operator Instructions) The next question comes from Matthew Biegler with Oppenheimer.

（操作員說明）下一個問題來自 Matthew Biegler 和 Oppenheimer。

We were just curious on time lines. Do you still think that a 6-month time line to a possible resolution is still on the table? Or is this likely a 2024 event?

我們只是對時間線感到好奇。您是否仍然認為 6 個月的時間線仍然可以解決問題？或者這可能是 2024 年的事件嗎？

As we're continuing the ongoing dialogue with the FDA, it's a little early to provide a clear definition of when the time line will get resolved. Certainly, we're in active conversations. We've really been encouraged by the dialogue that we're having with them since the interaction with them is cordial and very, very active. So our current guidance is assuming a rapid resolution of that time line. But exactly when that will get resolved, I don't want to guide to yet.

由於我們正在繼續與 FDA 進行對話，所以現在就何時解決這一問題給出明確的定義還為時過早。當然，我們正在進行積極的對話。我們與他們的對話確實讓我們深受鼓舞，因為與他們的互動是真誠的、非常非常活躍的。因此，我們目前的指導意見是假設該時間線能夠快速解決。但具體什麼時候能解決這個問題，我還不想透露。

Okay. That's fair. I wanted to maybe dial into a little bit more into what you just said about your interactions with the FDA. How would you describe them. Are they ongoing in collaborative? Or are you kind of just working now behind the scenes to, as you said to find an eligible patient population and then run some of the other non-toxicology studies? Or is this like a very cordial relationships that you have?

好的。這還算公平。我想進一步談談您剛才所說的與 FDA 的互動。你會如何描述它們。他們正在進行合作嗎？或者，正如您所說，您現在只是在幕後工作，尋找符合條件的患者群體，然後進行一些其他非毒理學研究？或者這就像你們之間非常友好的關係？

Yes. It's actually extremely cordial with the regulatory agency. As we discussed various thoughts with them, it has been a true partnership with them with real open discussion around their perception of the populations, which coincides with our perception of the populations that are at risk and it's not contentious in any way. It's actually a pleasure interacting with them as they provide guidance and thoughts on the population.

是的。它實際上對監管機構非常友善。當我們與他們討論各種想法時，我們與他們建立了真正的伙伴關係，圍繞他們對人群的看法進行了真正的公開討論，這與我們對處於危險之中的人群的看法一致，而且在任何方面都沒有爭議。與他們互動實際上是一種樂趣，因為他們為人們提供指導和想法。

(Operator Instructions) The next question comes from Judah Frommer with Credit Suisse.

（操作員說明）下一個問題來自瑞士信貸銀行的 Judah Frommer。

First, just curious from a clinical study perspective. Does changing the risk profile of the potentially addressable patient population kind of devalue any of the data you have thus far? Or is it more just about the commercial risk benefit profile here?

首先，只是從臨床研究的角度好奇。改變潛在可應對患者群體的風險狀況是否會降低您迄今為止擁有的任何數據的價值？或者這裡更多的是關於商業風險收益狀況？

Yes. Let me speak to the last part of that, the commercial value and then let Iain speak to the first part of the question, which has as you price it to the value of the data we have in hand. In this -- these initial studies defining a higher risk population as the FDA has requested. First of all, we think we'll -- based on the data we have in hand, we'll continue to see the robust increases in HbF that we've seen up-to-date. But more importantly, that's the study that we're requesting us to do first and that really doesn't speak to subsequent studies that we'd be doing that would be looking at the overall commercial opportunity for an oral small molecule activator of HbF, which we think still has an important place in the pharmacopia.

是的。讓我談談最後一部分，即商業價值，然後讓伊恩談談問題的第一部分，即根據我們手頭數據的價值對其進行定價。這些初步研究按照 FDA 的要求定義了較高風險人群。首先，我們認為，根據我們現有的數據，我們將繼續看到 HbF 的強勁增長。但更重要的是，這是我們要求我們首先做的研究，這確實與我們要做的後續研究無關，後續研究將著眼於 HbF 口服小分子激活劑的整體商業機會，我們認為它在藥典中仍然佔有重要地位。

As you know, overall commercial strategy often involves multiple kinds of trials and multiple kinds of patients. And this is just the first foray into a higher-risk population. Maybe I'll let Iain speak to whether have the applicability of the data we've generated today.

如您所知，整體商業策略通常涉及多種試驗和多種患者。這只是針對高風險人群的首次嘗試。也許我會讓伊恩談談我們今天生成的數據是否適用。

Yes. Thank you, Robert, and thanks, Jud. So I think in no way at all is this devalue to perceptions of the data that we've generated to date in the sickle cell patient population at doses of 2, 6 and 12 milligrams once daily. That population clearly is an affected sickle cell population. Some of them were also on concomitant hydroxyurea at that time, and we've seen robust increases in fetal hemoglobin in that population. So as we move forward into somewhat slightly different defined patient population, I don't think that there's any impact or adverse effects related to the previous data.

是的。謝謝你，羅伯特，也謝謝你，賈德。因此，我認為這根本不會貶低我們迄今為止在鐮狀細胞病患者群體中每日一次服用 2、6 和 12 毫克劑量的數據的看法。該群體顯然是受影響的鐮狀細胞群體。他們中的一些人當時還同時服用羥基脲，我們發現該人群的胎兒血紅蛋白急劇增加。因此，當我們進入定義略有不同的患者群體時，我認為與之前的數據相比不會產生任何影響或不利影響。

Okay. Is it fair to assume that if you're going up again, gene editing cell therapy type approaches that you would potentially be dosing higher to arrive at higher levels of HbF induction in a higher-risk population? Or is your sense that, again, which I know has been an area of contention historically. This 10% absolute induction bar might still be relevant in this higher-risk population.

好的。假設如果您再次採用基因編輯細胞療法類型，您可能需要更高劑量才能在高風險人群中達到更高水平的 HbF 誘導，這樣的假設是否公平？或者你的感覺是，我知道這在歷史上一直是一個有爭議的領域。這個 10% 絕對誘導棒可能仍然適用於這個高風險人群。

Yes. I don't think we see ourselves as going up against gene therapy and gene editing, we're using the way that they've defined their patient populations as a guideline as we move forward to define our patient population, bearing in mind that those procedures are associated with significant risks in and of themselves. So just a clarification there on how we're thinking of those particular populations.

是的。我不認為我們認為自己會反對基因治療和基因編輯，我們正在使用他們定義患者群體的方式作為我們前進定義我們的患者群體的指南，同時記住那些程序本身就存在重大風險。因此，我們只是澄清一下我們如何看待這些特定人群。

I don't think there's any bar on how much HbF induction we're looking for. I think clearly, as you've mentioned, the 10 is a number that has been thrown out there. I think in terms of the absolute percent that are helpful getting into the range of 20% to 30% is clearly being associated with clinical benefit using either genetic or pharmacological or a combination of those two approaches in the past.

我認為我們尋找多少 HbF 感應沒有任何障礙。我認為顯然，正如你所提到的，10 是一個被扔在那裡的數字。我認為，就有用的絕對百分比而言，進入 20% 至 30% 的範圍顯然與過去使用遺傳或藥理學或這兩種方法的組合的臨床益處相關。

And so I think getting into that range seems to be clearly beneficial and 30% and a little higher might be functionally curative in some extent -- to some extent. So we'll be evaluating the dose response as we move up potentially beyond 12 milligrams to evaluate the dose response on HbF.

因此，我認為進入這個範圍似乎顯然是有益的，30% 或更高一點可能在某種程度上具有功能性療效。因此，當我們可能將劑量提高到超過 12 毫克時，我們將評估劑量反應，以評估 HbF 的劑量反應。

This concludes the question-and-answer portion of the call. I will now turn the call back over to Fulcrum's CEO, Robert for closing remarks. Robert?

通話的問答部分到此結束。現在，我將把電話轉回 Fulcrum 的首席執行官 Robert 致閉幕詞。羅伯特？

Thank you, operator, and thanks to everyone who joined us this morning. Please stay safe and healthy. And I'm sure we'll all be talking to you all later. Thanks.

謝謝接線員，也感謝今天早上加入我們的所有人。請保持安全和健康。我確信我們稍後都會與你們交談。謝謝。

Thank you for participating. You may now disconnect. Goodbye.

感謝您的參與。您現在可以斷開連接。再見。